When an Antipsychotic Working as an Antidepressant, Do They Have a Therapeutic Window?

Background In psychopharmacology, therapeutic window is the drug concentration range that ensures safe and effective outcomes, with a higher risk of treatment failure outside this range. Dopamine receptor partial agonists (DRPAs) illustrate this concept, particularly in treating depression, as they require specific doses to balance efficacy and safety. Methods PubMed search focused on randomized controlled trials, open-label studies, and reviews evaluating aripiprazole, brexpiprazole, and cariprazine as augmentation therapies for major depressive disorder in adults. Results Clinical trials on aripiprazole, brexpiprazole, and cariprazine as antidepressant adjuncts show that effective doses are typically lower than antipsychotic doses: 2-10 mg for aripiprazole (vs 10-30 mg), 2-3 mg for brexpiprazole (vs 4 mg), and 1.5-3 mg for cariprazine (vs 1.5-4.5 mg). At subantipsychotic doses, partial agonists increase dopamine signaling, while at antipsychotic doses they reduce it to the drug’s intrinsic activity level (generally 25%-40% of maximal dopamine signal) which is generally inadequate for an antidepressant response. Conclusion DRPAs modulate the dopamine signaling depending on receptor occupancy: higher occupancy reduces signaling, while lower occupancy (when unoccupied receptors can interact with endogenous dopamine) enhances it. Understanding the drug-receptor relationship is crucial, since higher doses are not always more effective.